Much of the pain and disability displayed by patients with chronic rheumatoid and osteoarthritis stems from the destruction of articular cartilage which occurs in these diseases. The extracellular matrix of cartilage consists of a meshwork of collagen fibers that encloses and entraps proteoglycan and water. The resiliency of cartilage and its resistance to mechanical stress depend on the structural integrity of this matrix, particularly the large viscous proteoglycan aggregates that bind water. Destruction of cartilage in disease states results from enzymatic degradation of this matrix and proteolytic cleavage of the proteoglycan molecule appears to be a key event in this process. Many important details of proteoglycan structure are not known. The studies outlined in this proposal will provide detailed information about the structure and amino acid sequence of proteoglycan. Procedures are described for the cleavage of cartilage proteoglycan and the isolation of peptide fragments that are suitable for determination of their amino acid sequence. Our systematic studies of the antigenic determinants of cartilage proteoglycan will enable us to use immunological techniques, monospecific antibodies and immunoadsorbents, for the identification and isolation of proteoglycan fragments. Elucidation of the structure of normal proteoglycan will make it possible to determine the sites of cleavage of proteoglycan in chronic arthritis. This information will permit identification of the enzymes responsible for the degradation of cartilage and will allow the development of new methods of therapy for chronic arthritis.